One of the main objects of the aromatisation of foodstuffs for instance is to restore the original quality and nature of the flavour, aroma and taste of a given foodstuff material. Very often in fact the organoleptic properties of foodstuffs particularly diminish or are somehow modified in the course of the processes of freezing and storage, or during the modifications, such as cooking or baking, to which the foodstuffs are subjected in order to yield an edible material.
In the past the aromatisation was mainly achieved by using materials of natural origin. Nowadays, however, synthetic chemical compounds are used at an ever increasing rate. Said compounds possess the advantage of being available very often in unlimited quantities and at prices lower than those of the natural materials. Moreover, due to the fact that the flavouring character of a natural material is the result of the overall effect determined by the combination and interaction of each of its constituents, the effects achieved by said natural material are very often not as well reproducible as those obtained by the use of the pure synthetic compounds.
In the field of perfumery the man in the art has to solve a similar problem in attempting to reconstitute the olfactive notes of certain natural essential oils or extracts. The perfumer's creativity however is continually boosted by the finding of new synthetic compounds, the organoleptic properties of which will enable him to introduce unprecedented olfactive characters or nuances into new phantasy perfume compositions.
As a consequence, the problem that the chemical industry has to solve is to satisfy the increasing demand of new organoleptically interesting chemicals in order to better suit the specific needs of flavourists and perfumers.
It is known in the art that compounds of general formula ##STR4## wherein the side chain attached at position 1 of the ring contains one double bond in position 2' or 3'; the ring contains one endocyclic double bond in position 1 or 2,
or one exocyclic double bond in position 2, or two conjugated double bonds in position 1 and 3; PA1 n is zero or one; PA1 R.sup.1, r.sup.2 and R.sup.3 all represent hydrogen, or one of them an alkyl group and the others hydrogen; and PA1 R.sup.4, r.sup.5, r.sup.6 and R.sup.7 all represent hydrogen, or one of them an alkyl group and the others hydrogen
possess valuable organoleptic properties [see e.g. Swiss Pat. No. 509,399 and German Offenlegungsschrift No. 2,022,216]. The present invention provides a similar class of compounds as well as processes for preparing them.
It has now been found in fact that most of the compounds of formula I and certain of their related derivatives, forming together a class of compounds of general formula ##STR5## containing a double bond in the 2'-or 3'-position of the side chain and either two conjugated double bonds in the (endocyclic) 2- and 4-, or (exocyclic) 2- and 3- positions of the ring, or two non-conjugated double bonds in the 1- and 4- positions of the ring, and wherein n stands for the integers 1 or 2, possess interesting organoleptic properties and accordingly they can be used as flavouring ingredients for modifying, enhancing or improving the organoleptic properties of foodstuffs for men and animals beverages, pharmaceutical preparations and tobacco products, and for the preparation of artificial flavouring compositions, and/or as perfuming agents for the preparation of perfumes and perfumed products.
Although the chemical structure of said new compounds is closely related to that of the known above mentioned cycloaliphatic ketones, we have surprisingly found that the olfactive and flavouring characters of the presently disclosed compounds are sensibly different from those possessed by the known derivatives. This fact confirms once more the character of unpredictability which is related to the phenomena of olfaction and taste perception. It has in fact to be underlined that in spite of the number of theories which have been put forward in order to understand the detection of the specific signaling obtained in the presence or in the absence of a given chemical, in the present state of our knowledge we have to admit that no theoretical explanation enables to predict with certainty the odour or taste of a chemical compound [see e.g.: G. Ohloff, La Recherche, 2 [18,], 1068 (1971); Molecular Structure and Organoleptic Quality, S.C.I. Monograph No. 1, (1957)]. In actual experience it is known for instance that the organoleptic properties of ambrinol of formula ##STR6## comprising a double bond at one of the positions indicated by the dotted lines, vary according to the specific position of said double bond in the molecule, the .alpha.-isomer possessing the most pronounced ambra character [see: Helv. Chim. Acta, 42, 2233 (1959)].
The particular position of the double bond as well as its ethylenic stereoisomerism in an open chain aldehyde, such as hexenal, have a determining effect on the odour. Pure cis-3-hexenal possesses in fact a very strong fresh green odour whereas trans-2-hexenal possesses a less defined sweet smell [Helv. Chim. Acta, 45, 2567 (1962)].
The new cycloaliphatic ketones of the present invention possess a distinct olfactive not reminiscent of the flowers of certain plants such as those of the family of mignonette with a characteristic fresh, rosy, green, heady note. The minty note of ".beta.-damascenone", an analogous compound of formula ##STR7## [see: Helv. Chim. Acta, 53, 541 (1970)], is still present in the odour of some of the new compounds of the invention, but its character is less harsh, definitely sweeter and it is reminiscent of the typical odour of the aromatic leaves or sage.
In addition depending on the nature of the products into which the compounds of the invention are incorporated they may develop a variety of notes such as aromatic, floral, wax-like, leather-like or terpenic notes or any desired combination of the said notes.
It has been found that the new compounds mentioned above increase the strength and the diffusion power of the perfume compositions to which they are added and impart thereto, in many cases, a very natural richness. In some cases, they impart to the products, in which they are incorporated, a taste of red berries and can be used for improving the taste and the artificial flavour of strawberry, cranberry, cherry, red-currants or analogous compositions. The new ketones can surprisingly be used for increasing the taste and flavour of products such as honey or red wine.
The proportions in which the new compounds can be used in order to produce an interesting odoriferous effect vary within wide limits. In the preparation of perfume compositions, for example, interesting effects can be obtained by the presence of the new compounds in ratios of about 100 ppm to 5% of the total of the composition. Depending on the desired odoriferous effects the ratios of these ketones can be increased to about 10% and even more.
If the new compounds are used as flavouring agents or as additives destined to modify the organoleptic properties of foodstuffs for men and animals, beverages, pharmaceutical preparations and tobacco, their ratios can also vary within wide limits.
Interesting flavouring effects can e.g. be obtained by the use of 0.1 to 10 ppm of the new compounds, based on the product to be flavoured. However, these ratios can be increased beyond 10 ppm and reach 100 ppm if it is desired to obtain special flavouring effects. In the preparation of flavouring compositions by admixture of the new compounds with other flavouring agents the said compounds can be used in ratios of about 0.1 to 15% of the total of the composition. In many cases the average of the ratios used lies between 1 and 10% of the total weight of the composition. It is to be understood that the limits of the proportions given above do not represent absolute limits; in certain cases where special effects are desired the new compounds can be used in higher or lower concentrations than those mentioned above.
The expression "foodstuff" is used in this specification in its broadest sense. It also comprises products such as coffee, tea and chocolate.
One of the processes of the invention for the preparation of unsaturated alicyclic ketones having the formula I comprises acylating organo-metallic compounds having the formula EQU CH.sub.2 .dbd.CH--CH.sub.2 ME II
wherein ME represents a metal function, such as Li, Zn, Cd or Mg-halogen, by means of compounds having the formula ##STR8## wherein the dotted lines have the same meaning as above and the symbol X represents a group which is reactive under the reaction conditions, e.g. halogen, O-CO-alkyl, O-CO-aryl, O-alkyl or O-aryl.
According to a specific embodiment of the present invention the lithium derivative of 2-propenyl is used as the organo-metallic compound, and an ester of formula ##STR9## wherein the dotted lines have the meaning indicated above, is used as the compound of formula III. The alkyl radicals comprise e.g. methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl or iso-butyl radicals.
The compounds of formula III wherein the conjugated double bonds are in the 1- and 3-, (exocyclic) 2- and 3-, or (endocyclic) 2- and 4- positions of the ring, which are used as starting products in the process of the invention indicated above, can be prepared according to the process illustrated by the following scheme: ##STR10##
The cyclization of citral can be carried out by means of the usual techniques such as those described e.g. in Gildemeister & Hoffmann, "Die Aetherischen Oele", IIId, pp. 137-8, Akademie Verlag, Berlin (1966).
The dehydrogenation can be carried out by first halogenating the cyclohexene ring in the allyl-position and then dehydrohalogenating the product of the said halogenation. Common halogenating reagents, e.g. haloamides such as N-bromosuccinimide, N-bromoacetamide, N-dimethyl-bromohydantoin and their chlorinated analogues, can be used as the halogenating agents.
N-bromosuccinimide is preferably used according to the usual method [see Chem. Rev., 63, 21 (1963)].
The halogenation in the allyl-position can be carried out in an inert solvent. A chlorinated solvent such as CCl.sub.4, CHCl.sub.3, CH.sub.2 Cl.sub.2, dichloroethane, tetrachloroethane and trichloroethylene or a mixture of the said solvents can e.g. be used. The operation is preferably carried out at temperatures comprised between 20.degree. and 100.degree. C.
The dehydrohalogenation can be promoted by organic bases, e.g. tertiary amines such as morpholine, piperidine diethylaniline or dimethylaniline, and the dehydrohalogenation temperature is comprised between about 100.degree. and 150.degree. C.
According to the invention the compounds of formula IIIa, wherein the double bonds are in the (endocyclic) 2- and 4- positions of the ring, are prepared by a process which comprises treating an alkyl .alpha.-isoproylidene-acetoacetate in an inert organic solvent with a compound resulting from the reaction of a quaternary phosphorus salt having the formula EQU [CH.sub.2 .dbd.CH--CH.sub.2 --PR.sub.3 ].sup.+ X.sup.- IV
wherein R represents an alkyl or aryl radical and X represents a halogen such as e.g. chlorine, bromine or iodine, or a group such as e.g. C10.sub.4 or BF.sub.4, with a strong base.
Allyl-triphenyl-phosphonium chloride or bromide are preferably used as the quaternary phosphorus salt, and n-butyl-, methyl- or phenyl-lithium as the strong base.
It has been observed that the nature of the base used as well so the reaction conditions selected have no considerable influence on the yield of the final product obtained. However, it is preferred to prepare the allyl-triphenyl-phosphonium chloride or bromide by the reaction of triphenylphosphine with an excess of allyl chloride at reflux temperature (45.degree. C.). The treatment with a strong base can then be carried out at a temperature comprised between about -20.degree. and about +20.degree. C. n-Butyl-lithium is preferably used as the strong base, and the operation is carried out in an inert solvent such as ethers, e.g. ethyl ether, monoglyme, diglyme dioxan or tetrahydrofuran, or hydrocarbons, e.g. cyclohexane, hexane, benzene or toluene. Ethyl ether and hexane are preferably used.
According to the invention the compounds of formula IIIa, wherein the double bonds are in the 1- and 4- positions of the ring, having the formula ##STR11## are obtained by a process which comprises isomerizing a compound having the formula ##STR12## by means of a basic isomerization agent.
Strong organic bases, e.g. alkali metal alkoxides such as sodium, potassium or lithium methoxide or ethoxide are preferably used as the basic agents.
The isomerization reaction is preferably carried out in an alcoholic medium and at a temperature in the vicinity of the reflux temperature of the chosen solvent.
When treating the compounds of formula IIIa-I with an acidic agent there is obtained a mixture comprising in addition to the starting product, the compounds having the formulae ##STR13##
The separation of the constituents of the said mixture can be carried out by means of the techniques of separation commonly used in chemistry, e.g. by preparative vapour phase chromatography or by fractional distillation.
Strong organic or inorganic acids, e.g. p-toluenesulphonic acid, or a hydrogen halide, e.g. hydriodic or hydrochloric acid, can be used as the acidic agent. The reaction is preferably carried out by mixing the compound which must be isomerized with the chosen reagent which is dissolved in a inert solvent, e.g. benzene, toluene, cyclohexane or hexane, and at a temperature in the vicinity of the boiling temperature of the selected solvent.
The compounds of formula IIIa can moreover be obtained from isophorone derivatives according to a process which can be illustrated by the following reaction scheme: ##STR14##
The first step of the process illustrated above consists in a condensation between the mesityl oxide and an alkyl acetoacetate according to a known technique [see H. Rubinstein, J. Org. Chem. 27, 3886 (1962); J. D. Surmatis et al., J. Org. Chem., 35, 1053 (1970)].
The reduction of the 4-alkoxycarbonyl-isophorones can be carried out by means of reagents which are known to selectively reduce the carbonyl function to a secondary alcohol function, e.g. mixed hydrides of boron and an alkali metal, e.g. sodium or lithium [see e.g. H. O. House, "Modern Synthetic Reactions", Benjamin, Inc., New York (1965)].
The carbinols prepared according to the process described above can be obtained in pure state by a separation by means of vapour phase chromatography or fractional distillation. However, for economic reasons, it is preferred to proceed to the subsequent dehydration of the mixture of isomers such as it is obtained directly by the described reduction in the presence of an acidic catalyst.
As the acidic dehydration catalyst a strong acid, e.g. phosphoric or sulphuric acid, is the preferred one.
The mixture comprising the cyclic esters IIIa, if subjected to fractional distillation or separation by means of vapour phase chromatography, yields the esters in a pure state. The latter can be used as starting products for the preparation of the compounds of formula I according to one of the processes of the invention, or can be reduced by means of lithium-aluminium hydride to their corresponding alcohols having the formulae ##STR15## respectively.
According to a modification of the process described above the carbinols of formula VII can be prepared by a method which consists in
(a) epoxidizing a 4-alkoxycarbonyl-isophorone to yield a 3,3,5-trimethyl-4-alkoxycarbonyl-5,6-epoxy-cyclohexanone, PA0 (b) treating the resulting epoxy-ketone with hydrazine to yield a 1,3,3-trimethyl-2-alkoxycarbonyl-5-cyclohexen-1-ol, and PA0 (c) carrying out a rearrangement of the allyl double bond of the carbinol obtained according to (b) by means of an acidic agent.
The above process can be illustrated by the following scheme: ##STR16##
The preparation of the epoxy derivative as well as its conversion into the corresponding tertiary alcohol can be carried out according to known techniques [cf. in this respect Tetrahedron, 19, 1091 (1963) and J. Org. Chem., 26, 3615 (1961)].
The subsequent allyl rearrangement can be carried out in an acidic agent such as an inorganic protonic acid e.g. sulphuric acid [cf. for example Ann. der Chem., 618, 202 (1958)].
According to another process of the invention compounds having the formula ##STR17## containing either two non-conjugated double bonds in the 1- and 4- positions, or two conjugated double bonds in the 1- and 3-, (exocyclic) 2- and 3-, or (endocyclic) 2- and 4- positions of the ring, the double bonds being represented by the dotted lines, are obtained by isomerization of the compounds of formula I by means of an acidic or basic isomerization agent, or by means of heat.
Thus, when treating the ketone having the formula ##STR18## with a basic agent, e.g. with an alkali metal alkoxide, such as potassium tert-butoxide, the ketone of formula ##STR19## is obtained.
If compound Ia is treated with an acidic isomerization agent, for example with a protonic acid such as p-toluenesulphonic acid, or a hydrogen halide such as hydriodic acid, or with acidic diatomaceous earth, there is obtained a ketone having the formula ##STR20##
The isomerization of the double bond on the side chain is accompanied by a concomitant isomerization of the two conjugated double bonds of the hexadienic ring.
In particular, according to the process of the invention described above ketone VIb is obtained by the treatment of compounds having the formulae ##STR21## with a basic or acidic isomerization agent.
The same reagents as those mentioned above in connection with the preparation of VIa and VIb can be used as the isomerization agents.
The said isomerization can be carried out by treating the compound to be isomerized and the reagent in a dissolved form in an inert organic solvent, e.g. and aliphatic or cycloaliphatic hydrocarbon, an aromatic hydrocarbon a chlorinated hydrocarbon, or an ester or an ether. Tetrahydrofuran is the preferred solvent.
As mentioned above, the class of compounds described in the present specification comprises new compounds. As such, 2,6,6-trimethyl-1 -ethoxycarbonyl-1,4-cyclohexadiene, cis-and trans-2,6,6-trimethyl-1-[buten-2-oyl]-1,4-cyclohexadiene, 2,6,6-trimethyl-1-[buten-3-oyl]-1,4-cyclohexadiene, cis- and trans-2,6,6-trimethyl-1-[buten-2-oyl]-2,4-cyclohexadiene, 2,6,6-trimethyl-1-[buten-3-oyl]-2,4-cyclohexadiene, cis- and trans-2-methylene-6,6-dimethyl-1-[buten-2-oyl]-3-cyclohexene and 2-methylene-6,6-dimethyl-1-[buten-3-oyl]-3-cyclohexene should be mentioned .